Natural underlying mtDNA heteroplasmy as a potential source of intra-person hiPSC variability

Ester Perales-Clemente, Alexandra N. Cook, Jared M. Evans, Samantha Roellinger, Frank Secreto, Valentina Emmanuele, Devin Oglesbee, Vamsi K. Mootha, Michio Hirano, Eric A. Schon, Andre Terzic, Timothy J Nelson

Research output: Contribution to journalArticle

22 Scopus citations


Functional variability among human clones of induced pluripotent stem cells (hiPSCs) remains a limitation in assembling high-quality biorepositories. Beyond inter-person variability, the root cause of intra-person variability remains unknown. Mitochondria guide the required transition from oxidative to glycolytic metabolism in nuclear reprogramming. Moreover, mitochondria have their own genome (mitochondrial DNA [mtDNA]). Herein, we performed mtDNA next-generation sequencing (NGS) on 84 hiPSC clones derived from a cohort of 19 individuals, including mitochondrial and non-mitochondrial patients. The analysis of mtDNA variants showed that low levels of potentially pathogenic mutations in the original fibroblasts are revealed through nuclear reprogramming, generating mutant hiPSCs with a detrimental effect in their differentiated progeny. Specifically, hiPSC-derived cardiomyocytes with expanded mtDNA mutations non-related with any described human disease, showed impaired mitochondrial respiration, being a potential cause of intra-person hiPSC variability. We propose mtDNA NGS as a new selection criterion to ensure hiPSC quality for drug discovery and regenerative medicine.

Original languageEnglish (US)
JournalEMBO Journal
StateAccepted/In press - 2016



  • Global private mutation
  • Human iPSC
  • Intra-person variability
  • Mitochondrial DNA
  • Quality control
  • Universal heteroplasmy

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Perales-Clemente, E., Cook, A. N., Evans, J. M., Roellinger, S., Secreto, F., Emmanuele, V., Oglesbee, D., Mootha, V. K., Hirano, M., Schon, E. A., Terzic, A., & Nelson, T. J. (Accepted/In press). Natural underlying mtDNA heteroplasmy as a potential source of intra-person hiPSC variability. EMBO Journal.